Extracellular Vesicles From Mesenchymal Cells in the Treatment of Acute Respiratory Failure

Summary

This is a phase I/II, randomized, double-blind, placebo-controlled clinical trial that will evaluate the safety and potential efficacy of therapy with extracellular vesicles (EVs) obtained from mesenchymal stromal cells (MSCs), patients with moderate to severe acute respiratory distress syndrome due to COVID-19 or other etiology. Participants will be allocated to receive EVs obtained from MSCs or placebo (equal volume of Plasma-Lyte A). Blinding will cover the participants, the multidisciplinary intensive care team and the investigators.

Timeline

Start

2024-02-01

Primary completion

2025-06-01

Completion

2025-06-01

Publications

• Background Abels ER, Breakefield XO. Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake. Cell Mol Neurobiol. 2016 Apr;36(3):301-12. doi: 10.1007/s10571-016-0366-z. Epub 2016 Apr 6.
• Background Alipoor SD, Mortaz E, Garssen J, Movassaghi M, Mirsaeidi M, Adcock IM. Exosomes and Exosomal miRNA in Respiratory Diseases. Mediators Inflamm. 2016;2016:5628404. doi: 10.1155/2016/5628404. Epub 2016 Sep 25.
• Background Antunes MA, Braga CL, Oliveira TB, Kitoko JZ, Castro LL, Xisto DG, Coelho MS, Rocha N, Silva-Aguiar RP, Caruso-Neves C, Martins EG, Carvalho CF, Galina A, Weiss DJ, Lapa E Silva JR, Lopes-Pacheco M, Cruz FF, Rocco PRM. Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema. Front Cell Dev Biol. 2021 May 31;9:661385. doi: 10.3389/fcell.2021.661385. eCollection 2021.
• Background de Castro LL, Xisto DG, Kitoko JZ, Cruz FF, Olsen PC, Redondo PAG, Ferreira TPT, Weiss DJ, Martins MA, Morales MM, Rocco PRM. Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma. Stem Cell Res Ther. 2017 Jun 24;8(1):151. doi: 10.1186/s13287-017-0600-8.
• Background Cruz FF, Borg ZD, Goodwin M, Sokocevic D, Wagner DE, Coffey A, Antunes M, Robinson KL, Mitsialis SA, Kourembanas S, Thane K, Hoffman AM, McKenna DH, Rocco PR, Weiss DJ. Systemic Administration of Human Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles Ameliorates Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation in Immunocompetent Mice. Stem Cells Transl Med. 2015 Nov;4(11):1302-16. doi: 10.5966/sctm.2014-0280. Epub 2015 Sep 16.
• Background De Jong OG, Van Balkom BW, Schiffelers RM, Bouten CV, Verhaar MC. Extracellular vesicles: potential roles in regenerative medicine. Front Immunol. 2014 Dec 3;5:608. doi: 10.3389/fimmu.2014.00608. eCollection 2014.
• Background Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, Epple M, Horn PA, Beelen DW, Giebel B. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014 Apr;28(4):970-3. doi: 10.1038/leu.2014.41. No abstract available.
• Background Lanyu Z, Feilong H. Emerging role of extracellular vesicles in lung injury and inflammation. Biomed Pharmacother. 2019 May;113:108748. doi: 10.1016/j.biopha.2019.108748. Epub 2019 Mar 14.
• Background Lasser C, Jang SC, Lotvall J. Subpopulations of extracellular vesicles and their therapeutic potential. Mol Aspects Med. 2018 Apr;60:1-14. doi: 10.1016/j.mam.2018.02.002. Epub 2018 Feb 16.
• Background Naji A, Eitoku M, Favier B, Deschaseaux F, Rouas-Freiss N, Suganuma N. Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci. 2019 Sep;76(17):3323-3348. doi: 10.1007/s00018-019-03125-1. Epub 2019 May 4.
• Background Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013 Feb 18;200(4):373-83. doi: 10.1083/jcb.201211138.
• Background Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. Stem Cells Dev. 2020 Jun 15;29(12):747-754. doi: 10.1089/scd.2020.0080. Epub 2020 May 12.
• Background Silva JD, de Castro LL, Braga CL, Oliveira GP, Trivelin SA, Barbosa-Junior CM, Morales MM, Dos Santos CC, Weiss DJ, Lopes-Pacheco M, Cruz FF, Rocco PRM. Mesenchymal Stromal Cells Are More Effective Than Their Extracellular Vesicles at Reducing Lung Injury Regardless of Acute Respiratory Distress Syndrome Etiology. Stem Cells Int. 2019 Aug 21;2019:8262849. doi: 10.1155/2019/8262849. eCollection 2019.
• Background Shi MM, Yang QY, Monsel A, Yan JY, Dai CX, Zhao JY, Shi GC, Zhou M, Zhu XM, Li SK, Li P, Wang J, Li M, Lei JG, Xu D, Zhu YG, Qu JM. Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles. J Extracell Vesicles. 2021 Aug;10(10):e12134. doi: 10.1002/jev2.12134. Epub 2021 Aug 14.
• Background D'Souza-Schorey C, Schorey JS. Regulation and mechanisms of extracellular vesicle biogenesis and secretion. Essays Biochem. 2018 May 15;62(2):125-133. doi: 10.1042/EBC20170078. Print 2018 May 15.
• Background Tieu A, Lalu MM, Slobodian M, Gnyra C, Fergusson DA, Montroy J, Burger D, Stewart DJ, Allan DS. An Analysis of Mesenchymal Stem Cell-Derived Extracellular Vesicles for Preclinical Use. ACS Nano. 2020 Aug 25;14(8):9728-9743. doi: 10.1021/acsnano.0c01363. Epub 2020 Aug 4.
• Background Wiklander OP, Nordin JZ, O'Loughlin A, Gustafsson Y, Corso G, Mager I, Vader P, Lee Y, Sork H, Seow Y, Heldring N, Alvarez-Erviti L, Smith CI, Le Blanc K, Macchiarini P, Jungebluth P, Wood MJ, Andaloussi SE. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015 Apr 20;4:26316. doi: 10.3402/jev.v4.26316. eCollection 2015.
• Background Zhou T, He C, Lai P, Yang Z, Liu Y, Xu H, Lin X, Ni B, Ju R, Yi W, Liang L, Pei D, Egwuagu CE, Liu X. miR-204-containing exosomes ameliorate GVHD-associated dry eye disease. Sci Adv. 2022 Jan 14;8(2):eabj9617. doi: 10.1126/sciadv.abj9617. Epub 2022 Jan 12.
• Background Zhu YG, Feng XM, Abbott J, Fang XH, Hao Q, Monsel A, Qu JM, Matthay MA, Lee JW. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014 Jan;32(1):116-25. doi: 10.1002/stem.1504.

Drugs

Indications